TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

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1.0 Executive Summary

In PP#1F7845, Bayer Cropscience (Bayer) has petitioned for the increase of an existing tolerance

for combined residues of the fungicide trifloxystrobin [benzeneacetic acid, (E,E)-α-

(methoxyimino)-2-[[[[1-[3-(trifluoromethyl)phenyl]ethylidene] amino]oxy]methyl]-methyl ester] 

and the free form of its acid metabolite CGA-321113 [(E,E)-(methoxyimino)-[2-[1-(3-

(trifluoromethylphenyl)-ethylideneaminooxymethyl]-phenyl]acetic acid] in/on the following raw 

agricultural commodities (RAC):

Almond, hulls........................................................... 9.0 ppm

In addition, Bayer has petitioned for the removal of an existing tolerance for combined residues 

of trifloxystrobin in/on vegetable, root, except sugar beet, subgroup 1B, except radish (0.1 ppm).

The most recent human health risk assessment was conducted for use on imported coffee in 

which the hazard characterization and toxicity endpoints for risk assessment were reported 

(DP379110, N. Tsaur, 02/28/2011). Since then, a waiver request for a 28-day inhalation 

exposure toxicity study was submitted and denied, and a waiver request for a subchronic 

neurotoxicity (SCN) study was submitted and accepted. In addition, an immunotoxicity study 

has been submitted; preliminary examination of the data found no evidence of immunotoxicity. 

The hazard characterization and toxicity endpoints for risk assessments associated with this 

action remain unchanged. The details of the hazard characterization and the rationale for toxicity 

endpoint selection will not be repeated in this risk assessment. However, the salient features for 

the Food Quality Protection Act (FQPA) safety factor will be summarized.

A summary of the findings and a discussion of human health risk resulting from the proposed 

tolerance increase of trifloxystrobin are provided in this document. This assessment has been

conducted by Nancy Tsaur.

2.0 HED Recommendations

There are no data deficiencies that preclude establishment of an increased permanent tolerance 

for combined residues of trifloxystrobin in/on almond hulls.

The established tolerance for almond has been replaced by the established tolerance for nut, tree, 

group 14, and should be removed. In addition, the established tolerance for vegetable, root, 

except sugar beet, subgroup 1B, except radish, has been superseded by the established tolerance 

for vegetable, root, except sugar beet, subgroup 1B, and should be removed.

2.1 Data Deficiencies

Toxicology [870.7800 Immunotoxicity]

A Part 158.500 functional immunotoxicity study, previously required as a condition of 

registration, has been received and is currently in review.

Toxicology [870.3465 28-Day Inhalation Toxicity]
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Prior to 2010, the Agency frequently relied on oral toxicity studies to conduct inhalation risk 

assessments. In December 2009, the Agency sought expert advice and input from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) on issues 

related to this route to route extrapolation approach in the absence of an inhalation toxicity 

study (i.e. the use of oral toxicity studies for inhalation risk assessment). Based on the SAP’s 

recommendations in the March 2, 2010 Final Report 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html), the Agency has 

increased its focus on the uncertainties associated with route-to-route extrapolation and is 

presently requiring inhalation toxicity studies more frequently. The Agency has concluded 

that an inhalation toxicity study is required as a condition of registration to fully characterize 

the risk from inhalation exposure to trifloxystrobin.

2.2 Recommended Tolerances

Table 2.2. Tolerance Summary for Trifloxystrobin

Commodity

Tolerance (ppm) Comments

Established Correct Commodity Definition aProposed Recommended

40 CFR §180.609(a)(1)

Almond, hulls 3.0 9.0 9.0

Almond 0.04 -- Remove

A separate tolerance for almond is 

no longer needed because residues 

in this commodity will be covered 

by the established tolerance for 

nut, tree, group 14 at 0.04 ppm.

Vegetable, root, except 

sugar beet, subgroup 1B, 

except radish

0.10 -- Remove

This tolerance has been replaced 

by the established tolerance for 

vegetable, root, except sugar beet, 

subgroup 1B.

a Under 40 CFR §180.555(a).

3.0 Introduction

In PP#1F7845, Bayer has submitted a petition for a tolerance increase for trifloxystrobin in/on 

almond, hulls and the removal of tolerance in/on vegetable, root, except sugar beet, subgroup 

1B, except radish. With the petition, Bayer has submitted several draft labels detailing the 

proposed use pattern for the following trifloxystrobin products, two of which are mixed active 

ingredient (MAI) products:

50% WG formulation (Flint® Fungicide; EPA Reg. No. 264-777),

4.17 lb ai/gal SC formulation (Gem® 500 SC Fungicide; EPA Reg. No. 264-826),

25% WG formulation (Gem® Fungicide; EPA Reg. No. 264-781),

0.49 lb ai/gal SC MAI formulation (DistinguishTM 480 SC Fungicide; EPA Reg. No 264-

1027; also contains 3.51 lb ai/gal pyrimethanil), and

25% WG MAI formulation (Adament® 50 WG Fungicide; EPA Reg. No. 264-1052; also 

contains 25% tebuconazole).
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3.1 Chemical Identity

Trifloxystrobin is a strobilurin-class fungicide (also termed methoxyacrylates) that controls foliar 

fungal diseases and soilborne/seedling fungal diseases. It works by interrupting mitochondrial 

respiration in plant-pathogenic fungi, thus inhibiting spore germination and mycelial growth. It 

is a broad-spectrum preventative fungicide used for control of many plant diseases in various 

fruit, nut, vegetable, and field crops, including corn and soybean. Trifloxystrobin is described in 

Table 3.1.

Table 3.1. Trifloxystrobin Nomenclature

Chemical Structure

Empirical Formula C20H19F3N2O4 

Common name trifloxystrobin

Company experimental name BO17211 or CGA-279202

IUPAC name methyl (E)-methoxyimino-{(E)-α-[1-(α,α,α-trifluoro-mtolyl)ethylideneaminooxy]-o-tolyl}acetate

CAS name methyl (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-

(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetate

CAS Registry Number 141517-21-7

End-Use Products (EPs) Flint® Fungicide (50% ai); GemTM 500 SC (4.17 lb ai/gallon)

Chemical Class Strobilurin, methoxyacrylates

Known Impurities of Concern None

3.2 Pesticide Use Pattern

Reference:

- Trifloxystrobin. Application for Section 3 Registration to Increase the Tolerance on Almond Hulls, Reduce the 

Preharvest Interval for Use on Almond, and Remove the Tolerance for Vegetable, Root, Except Sugar Beet, 

Subgroup 1B, Except Radish. Summary of Analytical Chemistry and Residue Data. DP396514, Amelia Acierto, 

05/16/2012.

Under this action, Bayer is proposing to reduce the preharvest interval (PHI) for almonds from 

60 days to 14 days (except as noted for the MAI products). The proposed use patterns were 

compared with the accepted labels for all products; a summary of the use patterns are presented 

in Table 3.2 with proposed PHI changes denoted in italicized bold.

O

N

CF3

N

O

O

CH3

O

H3C

CH3
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Table 3.2. Summary of Directions for Use of Trifloxystrobin

Applic. 

Timing, Type, 

and Equip.

Formulation 

(EPA Reg. No.)

Applic. 

Rate

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

PHI a

Use Directions and Limitations

lb ai/A lb ai/A days

Almond

Foliar;

Broadcast or 

Airblast;

Ground (min. 

50 gal/A) or

aerial (min. 10 

gal/A)

50% WG

[264-777]

4.17 lb ai/gal SC

[264-826]

25% WG

[264-781]

0.062-

0.125 4 0.50 14

Apply at a 7- to 21-day RTI. 

Use of an adjuvant is not 

specified.

Foliar;

Broadcast;

Ground (min. 

50 gal/A) or

aerial (min. 15 

gal/A)

0.49 lb ai/gal SC 

MAI

[264-1027]

0.05-

0.10 3 0.30 30

Apply at a 7- to 14-day RTI. 

Use of an adjuvant is not 

specified.

Foliar;

Broadcast;

Ground (min. 

10 gal/A) or

aerial (min. 5 

gal/A)

25% WG MAI

[264-1052]

0.062-

0.125 4 0.50 35

Apply at a 7- to 14-day RTI. 

Use of an adjuvant is not 

specified.

a PHIs were formerly 60 days for all products.

The differences in the PHIs proposed for the two MAI formulations (30 and 35 days vs. 14 days) 

are associated with the second active ingredient in each product: minimum PHIs for almond are 

30 days for pyrimethanil and 35 days for tebuconazole.

The labels include separate use directions for pecan, pistachio, and tree nuts (50% WG, 4.17 lb 

ai/gal SC, and 25% WG formulations), for pistachio (0.49 lb ai/gal SC MAI formulation), and

for pistachio and tree nuts (25% WG MAI formulation); these use patterns remain unchanged.

The submitted use directions are adequate to allow evaluation of the residue data relative to the 

proposed reduction in PHI for use on almond; no additional data are required. Although 

adjuvant use is not specified for almond, the submitted data will support use of nonionic 

surfactants (NISs) for applications to almonds.

4.0 Hazard Characterization and Dose-Response Assessment

Reference:

- Trifloxystrobin. Human Health Risk Assessment for Proposed New Use on Imported Coffee. DP385972, Nancy J. 

Tsaur, 08/02/2011.

A detailed hazard characterization with a list of available toxicity studies for trifloxystrobin is 

presented in the previous risk assessment (DP385972, N. Tsaur, 08/02/2011). The submitted 
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toxicology studies are of good quality and provide sufficient information to determine whether 

trifloxystrobin poses a human health hazard. 

4.1 Safety Factor for Infants and Children (FQPA Safety Factor)

The toxicology and exposure data and have been evaluated and trifloxystrobin has been 

determined to be safe for infants and children, supporting the reduction of the FQPA safety 

factor to 1X.

4.1.1 Completeness of the Toxicology Database

The toxicity database for trifloxystrobin is complete with the exception of an immunotoxicity 

study and a 28-day inhalation toxicity study. A waiver for a subchronic neurotoxicity study has 

been granted. A preliminary examination of the recently submitted immunotoxicity study data 

provides no indication that trifloxystrobin affects the immune system and does not alter any of 

the PoDs for risk assessment. Although an inhalation study is needed to complete the database, 

there is no potential for residential inhalation exposure; therefore, there are no uncertainties with 

respect to inhalation risk. 

4.1.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in subchronic and chronic toxicity studies (rats, dogs, 

mice), in developmental toxicity studies (rats, rabbits), or in a reproductive toxicity study (rats). 

There is no concern for neurotoxicity for trifloxystrobin based on the available database, limited 

findings in an ACN study, and lack of neurotoxicity in other fungicides of the strobilurin class.

4.1.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no indication of increased quantitative or qualitative susceptibility to trifloxystrobin in 

rats or rabbits. In the prenatal developmental study in rats, there was no developmental toxicity 

at the limit dose. In the prenatal developmental study in rabbits, developmental toxicity was 

seen at a dose that was higher than the dose that caused maternal toxicity. In the multigeneration study, offspring and parental LOAELs are at the same dose level.

4.1.4 Residual Uncertainty in the Exposure Database

The exposure assessments will not underestimate the potential dietary (food and drinking water) 

or non-dietary exposures for infants and children from the use of trifloxystrobin. The main 

contribution to total aggregate exposure is from the dietary route. The acute dietary assessment 

was unrefined, assuming conservative upper bound inputs including 100% crop treated and 

tolerance-level residues. The chronic dietary assessment was partially refined, assuming 100% 

crop treated and tolerance-level residues for all commodities except for apples, grapes, and 

oranges where the average field trial residues were used. Although the chronic assessment 

included these minor refinements, the use of representative field trial data ensures that actual 

exposures/risks from residues in food will not be underestimated. The dietary drinking water 

assessment utilizes water concentration values generated by models and associated modeling 
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parameters which are designed to provide conservative, health protective, high-end estimates of 

water concentrations, and are not likely to be exceeded. In addition, the residential postapplication exposure assessment is based upon the residential SOPs employing surrogate study 

data, including conservative exposure assumptions based on Day 0 dermal contact to turf treated 

at the maximum application rate. There is no potential for inhalation exposure. These data are 

reliable and are not expected to underestimate risk to adults or children. The residential SOPs 

are based upon reasonable “worst-case” assumptions and are not expected to underestimate risk.

4.2 Summary of Points of Departure and Endpoints Used in Human Risk Assessment

The summary of toxicological doses and endpoints supporting this petition remain unchanged 

and have been summarized in the previous human health risk assessment (DP385972, N. Tsaur, 

08/02/2011) as well as the most recent Federal Register Notice (EPA-HQ-OPP-2011-0456-0004, 

FRN Vol. 76, No. 217, pp. 69648, 11/09/2011).

5.0 Dietary Exposure and Risk Assessment 

Reference:

- Trifloxystrobin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk 

Assessment for the Petition for Establishment of a Tolerance on Imported Coffee. DP387201, Nancy J. Tsaur, 

07/13/2011.

There were no appropriate toxicological effects attributable to a single exposure (dose) for the 

general population or any other population subgroups other than females 13-49 years old. The 

most recent acute and chronic dietary exposure assessments conducted for trifloxystrobin would 

not be affected by the proposed tolerance increase for almond hulls. The results of both acute 

and chronic dietary exposure analyses remain unchanged and are reported in Table 5.0. The 

acute dietary (food + drinking water) assessment was unrefined, and the chronic dietary (food + 

drinking water) assessment was partially refined, assuming 100% crop treated and tolerancelevel residues for all commodities except for apples, grapes, and oranges where the average field 

trial residues were used. Trifloxystrobin is classified as “not likely to be carcinogenic to 

humans” and thus cancer risk is not expected.

Table 5.0. Summary of Dietary Exposure and Risk for Trifloxystrobin

Population Subgroup

Acute Dietary

(Food and Drinking Water)

Chronic Dietary

(Food and Drinking Water)

Dietary Exposure % aPAD* Dietary Exposure % cPAD*

mg/kg/day mg/kg/day

General U.S. Population N/A 0.013067 34

Children 1-2 years old 0.024165 64

Females 13-49 years old 0.047424 1.9 0.012206 32

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Reference:

- Occupational and Residential Risk Assessment for Section 3 Petition to Register New Uses of Trifloxystrobin on 

Barley, Oats, Sweet Corn, and for the Treatment of Sweet Corn Seed. DP319193, Jack Arthur, 07/14/2005.
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According to the labels, the currently registered residential products are restricted to use by 

Certified Pest Control Operators (PCOs) only. Therefore, an assessment for residential handlers 

was not conducted. Additionally, residential risk estimates cannot be combined because the 

toxic effects are different via different routes of exposure. Thus, the risk estimates resulting 

from post-application exposure scenarios remain unchanged from the previous assessment and 

are summarized in Table 6.0.

Table 6.2. Short- and Intermediate-Term Residential Post-Application Exposure and Risk Estimates for 

Trifloxystrobin

Population

Post-Application Exposure 1

mg/kg/day

Residential PostApplication Total 

Exposure

mg/kg/day

MOE

Dermal Inhalation Oral

Adult 0.079 NA NA 0.079 1300

Child 0.13 NA NA 0.13 770

NA NA 0.0051 0.0051 750

1

Post-application exposure represents high end incidental oral exposure for the relevant exposure duration (hand-to-mouth).

7.0 Aggregate Exposure/Risk Characterization

The aggregate risk calculation remains unchanged since the last risk assessment because the 

proposed tolerance increase for almond hulls does not change the dietary risk estimates, and 

residential risk estimates remain unchanged. Chronic exposures via the dietary (food and 

drinking water) route are summarized in Section 5.0. Short- and intermediate-term risk estimates 

are summarized in Table 7.0. An aggregate cancer assessment was not conducted because 

trifloxystrobin is classified as “not likely to be carcinogenic to humans.”

This assessment has taken into consideration the changes in the new Residential Standard 

Operating Procedures (SOPs) to be implemented in January of 2012. HED finds no changes that 

would affect the aggregate safety finding and confirms that there are no risks of concern 

resulting from setting a higher tolerance of 9.0 ppm for trifloxystrobin in/on almond, nor from 

utilizing the new Residential SOPs to estimate residential exposure and risk.

Table 7.0. Short- and Intermediate Term Aggregate Risk Calculations

Population

Short- and Intermediate-Term Scenario

NOAEL LOC 1

Average 

Food and 

Water 

Exposure

Residential 

Dermal 

Exposure 2

Residential 

Oral 

Exposure 2

Total 

Exposure 3

Aggregate 

MOE (food, 

water, and 

residential) 4

mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day

Adult 100 100 0.013067 0.079 NA 0.092067 1,100

Children (Dermal)

1-2 years old 100 100 0.024165 0.13 NA 0.154165 650

Children (Oral)

1-2 years old 3.8 100 0.024165 NA 0.0051 0.029265 130

1 LOC = level of concern.

2 Residential Dermal and Oral Exposures cannot be combined (Table 6.2).

3 Total Exposure = Avg Food & Water Exposure + Residential Exposure.

4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)].